Immunohistochemistry of LAMP-2 and adipophilin for phospholipidosis in liver and kidney in ketoconazole-treated mice

Asaoka, Yoshiji; Togashi, Yuko; Imura, Naoko; Sai, Takafumi; Miyoshi, Takefumi; Miyamoto, Yohei

doi:10.1016/j.etp.2012.11.008

Cited by 14 publications

(11 citation statements)

References 22 publications

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“…These lipid-like vacuoles are in contrast to glycogen-like vacuoles where there is irregular lacy intracytoplasmic clearing and no nuclear displacement. Phospholipidosis in rodent livers can be induced by a number of cationic amphiphilic drugs, and affected hepatocytes have variably sized clear cytoplasmic vacuoles that cannot be unequivocally distinguished from lipid based on morphology alone (38,39). Although we did not see elevated liver triglyceride levels in these animals, it is possible that this may have appeared with a longer duration of treatment.…”

Section: Table 2 Summary Of Tissue Retinoid Levels From Experimentscontrasting

confidence: 49%

Inhibition of Retinoic Acid Biosynthesis by the Bisdichloroacetyldiamine WIN 18,446 Markedly Suppresses Spermatogenesis and Alters Retinoid Metabolism in Mice

Paik¹,

Haenisch²,

Müller³

et al. 2014

Journal of Biological Chemistry

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Section: Table 2 Summary Of Tissue Retinoid Levels From Experimentscontrasting

confidence: 49%

Inhibition of Retinoic Acid Biosynthesis by the Bisdichloroacetyldiamine WIN 18,446 Markedly Suppresses Spermatogenesis and Alters Retinoid Metabolism in Mice

Paik¹,

Haenisch²,

Müller³

et al. 2014

Journal of Biological Chemistry

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“…Drug-induced phospholipidosis (PL) is a phospholipid storage disorder caused by the formation of phospholipid-drug complexes in lysosomes, characterized as lamellar bodies by transmission electron microscopy [1]. Although the molecular mechanisms underlying drug-induced PL are still not fully understood, they are thought to be associated with the formation of an indigestible phospholipid-drug complex, the suppression of phospholipase activity, disrupting membrane fluidity [2], and an imbalance between the production and degradation of phospholipids [3,4].…”

Section: Introductionmentioning

confidence: 99%

Use of 3D Human Liver Organoids to Predict Drug-Induced Phospholipidosis

Lee

Han

Lee

et al. 2020

IJMS

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Drug-induced phospholipidosis (PL) is a storage disorder caused by the formation of phospholipid-drug complexes in lysosomes. Because of the diversity of PL between species, human cell-based assays have been used to predict drug-induced PL in humans. We established three-dimensional (3D) human liver organoids as described previously and investigated their liver characteristics through multiple analyses. Drug-induced PL was initiated in these organoids and in monolayer HepG2 cultures, and cellular changes were systemically examined. Organoids that underwent differentiation showed characteristics of hepatocytes rather than HepG2 cells. The organoids also survived under PL-inducing drug conditions for 48 h and maintained a more stable albumin secretion level than the HepG2 cells. More cytoplasmic vacuoles were observed in organoids and HepG2 cells treated with more potent PL-induced drugs, but to a greater extent in organoids than in HepG2 cells. Lysosome-associated membrane protein 2, a marker of lysosome membranes, showed a stronger immunohistochemical signal in the organoids. PL-distinctive lamellar bodies were observed only in amiodarone-treated organoids by transmission electron microscopy. Human liver organoids are thus more sensitive to drug-induced PL and less affected by cytotoxicity than HepG2 cells. Since PL is a chronic condition, these results indicate that organoids better reflect metabolite-mediated hepatotoxicity in vivo and could be a valuable system for evaluating the phospholipidogenic effects of different compounds during drug development.Int. J. Mol. Sci. 2020, 21, 2982 2 of 18 stages [6]. PL can occur in target organs without organ-related toxicity or physiological consequences [7], however, there are cases in which PL is observed with target organ toxicity [8]. Due to the uncertainty of the toxicological outcome of PL, drug-induced PL discovered in preclinical studies can have a detrimental impact on pharmaceutical development and delay the process. Fatal genetic disorders such as Niemann-Pick disease and Tay-Sachs disease [9,10] associated with PL have been described in humans, as has cell membrane damage leading to cell death. And other hepatic [11,12] cardiac [13,14], renal [15,16] pulmonary [17,18], eye [19], nervous [20], and skin [21] toxicities related to PL are known.Although drug-induced PL can be detected preclinically using in vivo systems such as animal models [3,[22][23][24], these types of studies are expensive, time-consuming, can raise ethical issues, and may not have specific toxicological relevance to humans. It has also been recommended that compounds that can lead to PL in humans should be identified and screened out in the early stages of drug discovery [25]. PL can be observed in any organ in the body, but the lung, liver, kidney, brain, spleen, and other lymphoid tissues are the most commonly involved sites [26]. To identify chemicals that provoke PL in humans, cell-based in vitro assays using various human liver cell types, such as HepG2 cells, HuH7 cells, and human pri...

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“…Liver is a principal site for drug metabolism and PLD was often reported in liver with foamy vacuoles and lipid droplets found in hepatocytes (Goldman et al, 1985; Asaoka et al, 2013). PEG-GO enhancement on Ifenprodil induced PLD was confirmed in a series of hepatocyte related models, including HepG2 cell line, primary hepatocytes and hepatocyte spheroids.…”

Section: Discussionmentioning

confidence: 99%

Detection of nanocarrier potentiation on drug induced phospholipidosis in cultured cells and primary hepatocyte spheroids by high content imaging and analysis

Zhang

Yang

Liu

et al. 2018

Toxicology and Applied Pharmacology

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Considerable effort has been made to develop nanocarriers for controlled drug delivery over the last decade, while it remains unclear how the strength of adverse drug effect will be altered when a drug is loaded on the nanocarrier. Drug-induced phospholipidosis (DIP) is characterized with excessive accumulation of phospholipids in cells and is common for cationic amphiphilic drugs (CAD). Previously, we have reported that PEGylated graphene oxide (PEG-GO) loaded with several CAD can potentiate DIP. In current study, we extended our study on newly identified phospholipidosis (PLD) inducers that had been identified from the Library of Pharmacologically Active Compounds (LOPAC), to investigate if PEO-GO loaded with these CAD can alter DIP. Twenty-two CAD were respectively loaded on PEG-GO and incubated with RAW264.7, a macrophage cell line. The results showed that when a CAD was loaded on PEG-GO, its strength of PLD induction can be enhanced, unchanged or attenuated. PEG-GO loaded with Ifenprodil exhibited the highest PEG-GO potentiation effect compared to Ifenprodil treatment alone in RAW264.7 cells, and this effect was confirmed in human hepatocellular carcinoma HepG2, another cell line model for PLD induction. Primary hepatocyte culture and spheroids mimicking in vivo conditions were used to further validate nanocarrier potentiation on DIP by Ifenprodil. Stronger phospholipid accumulation was found in PEG-GO/Ifenprodil treated hepatocytes or spheroids than Ifenprodil treatment alone. Therefore, evidences were provided by us that nanocarriers may increase the adverse drug effects and guidance by regulatory agencies need to be drafted for the safe use of nanotechnology in drug delivery.

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Immunohistochemistry of LAMP-2 and adipophilin for phospholipidosis in liver and kidney in ketoconazole-treated mice

Cited by 14 publications

References 22 publications

Inhibition of Retinoic Acid Biosynthesis by the Bisdichloroacetyldiamine WIN 18,446 Markedly Suppresses Spermatogenesis and Alters Retinoid Metabolism in Mice

Inhibition of Retinoic Acid Biosynthesis by the Bisdichloroacetyldiamine WIN 18,446 Markedly Suppresses Spermatogenesis and Alters Retinoid Metabolism in Mice

Use of 3D Human Liver Organoids to Predict Drug-Induced Phospholipidosis

Detection of nanocarrier potentiation on drug induced phospholipidosis in cultured cells and primary hepatocyte spheroids by high content imaging and analysis

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